Diagnosis and Prevention of Fetal Heart Disease

ABSTRACT

The present invention relates to a method for assessing the likelihood of the presence or formation of fetal heart disease (such as HLHS) in a fetus. In this methodology, the mother, either before or during pregnancy, is tested for the presence of anti-strep antibodies. If positive, the fetus is evaluated and monitored for the presence of fetal heart disease; the fetus can be treated, if appropriate. In addition, either prior to pregnancy or during the first trimester, the mother can be treated to prevent the formation of such antibodies or to neutralize their presence or effect fetal heart tissue.

CROSS REFERENCE TO RELATED APPLICATION

This application is related to and claims priority from U.S. ProvisionalPatent Application No. 60/723,742, Eghtesady, filed Oct. 5, 2005,incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to a methodology for assessing thelikelihood that a fetus will be at enhanced risk to develop fetal heartdisease. The methodology utilizes maternal testing for an antecedentstreptococcal infection. The invention also encompasses a method forpreventing the formation of such heart disease.

Hypoplastic left heart syndrome (HLHS) and its variants (includingaortic stenosis and mitral stenosis) are severe congenital heart defectswith substantial associated morbidity and mortality. The primary diseaseprocess involves damage and underdevelopment of the left-side heartstructures such that the end result is an abnormal heart not capable ofsupporting the normal circulation of a newborn. Treatment currentlyentails either high risk and costly multistage reconstructive surgery orheart transplantation, all commencing immediately after birth. Theseleft-side heart structure defects, as well as similar right-side heartstructure defects, are collectively referred to herein as “fetal heartdisease.”

The etiology of this and associated conditions is not currently known. Agenetic etiology has been proposed based on limited familial occurrence,but no genetic mutation has been attributed to this disease or itsvariants. Indeed, HLHS and associated conditions have been linked tonearly every single chromosomal and syndromic anomaly. Although lesscommon, congenital heart defects affecting the right-side of the heartresult in similar underdevelopments of the right-side heart structures(such as pulmonary stenosis or pulmonary atresia or tricuspid valvestenosis). This can also result in disabling heart disease of thenewborn and, similar to the previously discussed defects, their etiologyremains unknown. It would be a very positive development to understandthe etiology of fetal heart disease so that a given fetus'spredisposition to such condition could be evaluated and, if thepredisposition is high, appropriate palliative measures can be taken,perhaps while the fetus is still in utero.

SUMMARY OF THE INVENTION

The present invention, therefore, relates to a method for assessing thelikelihood of the presence or formation of fetal heart disease (such asHLHS) in a fetus, comprising testing for the presence of anti-strepantibodies (group A, C or G) in a woman pregnant with said fetus, saidwoman being asymptomatic for a strep infection at the time of the test.If the testing is positive for the presence of strep A antibodies, thenthe fetus is evaluated and monitored for the presence of HLHS or otherfetal heart disease. Alternatively, the fetus can be treated througheither treatment of the mother for an asymptomatic strep infection orthrough immunologic treatment of either the mother, fetus or both, forexample, with such agents as intravenous immunoglobulin (IVIG).

The present invention also relates to a method for assessing thelikelihood of presence or formation of fetal heart disease (such asHLHS) in a fetus, comprising testing for the presence of anti-strepantibodies in a woman pregnant with said fetus and, if positive,evaluating and monitoring said fetus for the presence of fetal heartdisease.

Finally, the present invention relates to a method for preventing theformation of fetal heart disease (such as HLHS), comprising testing forthe presence of anti-strep antibodies in a woman who is not pregnantand, if the testing is positive, treating for the presence of anti-strepantibodies in said woman prior to her becoming pregnant or within thefirst trimester of her pregnancy.

DETAILED DESCRIPTION OF THE INVENTION

The crux of the present invention is the concept that the pathogenesisof fetal heart disease, as described above, is related to an immunologicinjury to the fetal heart during development from a group of maternalantibodies that cross the placenta during gestation. These antibodieswere generated in the mother previously in response to an antecedentstreptococcal infection, most likely of a pharyngeal location. In themother, the previous infection (for example, “strep throat”) would leadto development of the antibodies that were originally designed todestroy the bacteria responsible for the step throat, the group Abeta-hemolytic streptococcus, or the group C and G beta-hemolyticstreptococcus. As used herein, the phrase “anti-strep antibodies” isintended to encompass the Group A, C or G antibodies, as well as anyother antibodies which form in the mother in response to a strepinfection. By chance, these antibodies have the potential to cross-reactwith fetal heart tissue, particularly in a male fetus. The resultinginjury to the cardiac valves and heart muscle leads secondarily toabnormal blood flow through the left-side heart structures, causing theobserved pathologies.

The concept of strep throat infection leading to heart disease has someprecedent; it the cornerstone of the rationale for treatment to preventrheumatic heart disease and fever in children and adults. However, theconcept that such an event could be participating in the pathogenesis offetal heart disease has never been put forward previously. In rheumaticheart disease, for unknown reasons, the predominant disease processinvolves the left-side heart structures, the right-side (or both sides)involvement of the heart has also been reported. The present inventorbelieves that the same predisposition in the fetus explains thepreponderance of left-side fetal heart disease and the less frequentright-side heart disease. Further, there is precedent for transplacentalinjury to the fetus via an immunologic mechanism as seen in congenitalheart block or fetal thrombocytopenia and associated fetal loss.

It is proposed herein that unlike current popular thinking (geneticetiology), these fetal heart diseases and perhaps even the commonbicuspid aortic valve, the primary source of aortic stenosis thatultimately affects the adult population, and coarctation of the aorta,are manifestations of the same disease process. This would suggest thata significant portion of heart disease affecting the population may infact be attributed to such an early mechanism that may continue intoadulthood through subsequent repeated exposure of the individual to thestreptococcus species.

Thus, in executing the method of the present invention, a test for thepresence of strep antibodies and strep infection may be administered toa woman who is not, at the time of the test, symptomatic for a strepinfection. Such tests are known in the art. For example, Cunningham,Clin. Microbiol. Rev. 13: 470-511 (2000) describes the standard throatculture procedure. Further, Corneli, Curr. Infect. Dis. Rep. 6: 181-186(2004), and Sheeler, et al, J. Am. Board Fam. Prac. 15: 261-265 (2002)discuss the rapid antigen testing technique and compare it to throatcultures. The woman who is tested may be pregnant at the time of thetest (for determining the risk of fetal heart disease to that particularfetus), or may not be pregnant (for the purpose of assessing the risk offetal heart disease to fetuses of future pregnancies). If the woman ispregnant and the strep tests are positive, then the fetus can beevaluated and monitored for the presence or development of fetal heartdisease, such as HLHS. If interested, the pregnant women can be treatedwith antibiotics to diminish the risk of developing a fetus withaffected heart disease (preventive therapy). If fetal heart disease ispresent in the fetus, then appropriate treatment techniques can beutilized to mitigate the condition, including such immunologic therapyas administration of IVIG (or a more specifically-targeted material),steroids, and immune system modulators to the mother, fetus or both.Alternatively, a mechanism to clear the placental circulation of theseantibodies, for example through plasmapheresis of either mother orfetus, may help mitigate continuing injury to the fetal heart. Othertreatment approaches could include a Strep vaccine developed and usedwith the purpose of being given to women of reproductive age. Similarly,antibodies or reagents could be developed that would function byinterfering with the passage of antibodies across the placenta or withthe interaction of the antibodies with fetal heart tissue antigens.Blood or amniotic fluid samples from the fetus may also be tested forpresence of these anti-strep antibodies to further confirm presence orabsence of disease or for assessing the effects and adequacy of anytherapy on the baby. If the woman is not pregnant, then appropriatetreatment can be administered prior to her next pregnancy or during theearly part of that pregnancy (e.g., the first trimester).

The implications of the present invention include the fact thatattributable heart defects may be preventable through screening ofpregnant mothers for the presence of streptococcal infection or acarrier state for strep antibodies. Further, development of vaccines forstrep could then be applied to this particular population or others atrisk to prevent the development or progression of various heartdiseases. Further, the treatment of these heart defects may be feasiblein utero through implementation of IVIG, antibiotics, plasmapheresis oralternative immunologic therapy, or a combination thereof.Simultaneously, a similar protocol may be combined with more invasivefetal therapeutic measures (such as catheter intervention) to achievesuccessful prenatal therapy. The present invention would allow for theidentification of mothers potentially at risk for giving birth tochildren with fetal heart disease. This would allow for earlyintervention, or perhaps even therapy, through antibody therapies thatwould interfere with the pathogenic antibodies, thereby reducing therisk of fetal heart conditions in an existing pregnancy or futurepregnancies.

1. (canceled)
 2. (canceled)
 3. (canceled)
 4. (canceled)
 5. (canceled) 6.A method for preventing the formation of fetal heart disease, comprisingtesting for the presence of anti-strep antibodies in a woman who is notpregnant and, if said test is positive for the presence of suchanti-strep antibodies, treating for the presence of anti-strepantibodies in said woman prior to her becoming pregnant or within thefirst trimester of her pregnancy.
 7. (canceled)
 8. The method accordingto claim 6 wherein the fetal heart disease relates to damage to theleft-hand heart structures.
 9. The method according to claim 8 whereinthe fetal heart disease is HLHS.
 10. (canceled)
 11. (canceled)
 12. Themethod according to claim 6 wherein the treatment is selected fromadministration of strep vaccines, administration of immune systemmodulators, plasmaphoresis to remove the antibodies, interfering withthe passage of the antibodies across the placenta, interfering with theinteraction of the antibodies with fetal heart tissue antigens, andcombinations thereof.